Friedreich ataxia (FRDA) is an autosomal recessive degenerative disorder characterized by ataxia, dysarthria, sensory loss, diabetes, and cardiomyopathy (1,2). Patients with FRDA have genetic abnormalities in a gene now known as FRDA; 95% of patients carry two copies of an expanded intronic GAA repeat, whereas 5% carry an expanded GAA repeat on one allele in conjunction with a point mutation in FRDA on the other allele. The length of the shorter GAA repeat inversely correlates with age of onset in large series of patients (2,3). The gene product (frataxin) involved in FRDA is localized to the mitochondrion, and its absence causes mitochondrial iron accumulation (4). This suggests possible therapies for FRDA, but there is presently no widely accepted measure for longitudinal clinical outcomes assessment in patients with FRDA. Analysis of candidate clinical outcome measures is necessary for use in long-term clinical trials.
Afferent and efferent visual dysfunctions are frequent manifestations of FRDA. Most patients with FRDA have normal high-contrast visual acuities, but a subpopulation (5–30%) may have mildly decreased visual acuity, usually to the level of 20/30 (1,5–9). In most cases, this is believed to reflect optic neuropathy, and pathologic abnormalities have been found in the lateral geniculate nuclei of patients with FRDA. A few patients have severe visual loss from optic neuropathy (10,11). A variety of eye movement abnormalities, including fixation instability, also cause visual dysfunction in patients with FRDA (12–14). Therefore, a combination of afferent and efferent visual abnormalities is likely to contribute to the neurologic dysfunction of FRDA, and a clinical outcome measure that captures all aspects of FRDA-related visual loss is needed.
In contrast to classically designed mechanisms for assessing ataxia, visual function can be quantitatively assessed using convenient, readily available clinical outcome measures. Recently, contrast letter acuity testing has been explored as a potential quantitative measure for detecting visual dysfunction in patients with multiple sclerosis, a disorder characterized by functional limitations and neurologic progression analogous to FRDA (15). The purpose of the current study was to examine the capacity for binocular contrast letter acuity testing, using Low-contrast Sloan Letter Charts (LCSLC) to identify visual dysfunction in patients with FRDA. To accomplish this, LCSLC scores for FRDA patients were compared with those of age-matched visually asymptomatic volunteers (controls). The relation of LCSLC scores to high-contrast visual acuity and to other aspects of neurologic function in FRDA was also determined.
Selection of Participants
Study protocols were approved by the Institutional Review Board at the University of Pennsylvania. Thirty-two adult patients with genetically confirmed (n = 30) or clinically diagnosed FRDA (n = 2) were invited at the time of their clinical evaluation to participate in testing using the Low-contrast Sloan Letter Charts (LCSLC) as described previously; these charts have gray letters of progressively smaller sizes on a white background (15–18). Visually asymptomatic volunteers (controls), who were category-matched for median age with FRDA patients, also were invited to participate. Volunteers were selected from among staff and faculty members of the University of Pennsylvania and were eligible if they had no known history of neurologic or ophthalmologic disease other than refractive error.
Contrast letter acuity testing
Binocular contrast letter acuity testing was performed as described previously using LCSLC (Precision Vision, LaSalle, IL) (15). The LCSLC have a standardized format based on that of the Bailey-Lovie and ETDRS (Early Treatment Diabetic Retinopathy Study) visual acuity charts, the standard charts used for acuity measurement in ophthalmology clinical trials (16–18). For this study, the 5%, 1.25%, and 0.6% contrast charts were used. High-contrast visual acuity was also tested using the 100% contrast chart; binocular Snellen equivalents were recorded. Patients were positioned 2 meters from the charts and tested using standardized protocols based on ETDRS visual acuity testing (15,19–20). Using these protocols, patients were asked to identify single letters, starting on the top line of each chart, reading left to right. Letter-by-letter scoring (number of letters identified correctly per chart) was used, resulting in a letter score (maximum 60) for each chart (21–22). Uniform, overhead lighting (80–100 foot candles on white background of charts) was used for each testing session and accomplished using standard fluorescent office lighting. Participants wore their usual corrective lenses during testing. Binocular testing was used in this study to minimize patient fatigue and to best capture visual function as is present for daily activities.
The number of letters identified correctly on each chart was recorded (maximum 60/chart). An aggregate score including the three low-contrast charts and the high-contrast visual acuity chart was also calculated. The binocular Snellen visual acuity equivalent was determined based on the lowest line of the high-contrast (100%) chart for which the participant identified three or more letters correctly. Comparisons of LCSLC scores between FRDA and control groups were performed using the Wilcoxon rank sum test.
Demographic data and disease features for patients with FRDA were recorded, including length of the shorter GAA repeat, ambulation status, age, and disease duration. GAA repeat lengths were available in 29 patients as determined by commercial DNA analysis. In one patient, GAA repeat length was presumed to be identical to the genetically confirmed sibling. A second patient, who carried a C-terminal point mutation, was treated as having a repeat length of 1000, consistent with the expected severity of C-terminal point mutations (23). Ambulation status was categorized based on whether the patient walked unassisted, used an assistive device (cane or walker), or used a wheelchair. Spearman rank correlations were used to assess the relation of LCSLC scores to FRDA disease features such as triplet repeat length, age, and disease duration. Linear regression analysis was used to further examine the relation of LCSLC scores to ambulation status while accounting simultaneously for patient age.
Demographic characteristics of FRDA patients and visually asymptomatic volunteers (controls) were compared. Age was similar between the groups (for patients: median = 25.5 years, range = 10–57 years; for controls, median = 31 years, range = 24–50 years;P = 0.15 by Wilcoxon rank sum test). Among patients with FRDA, the length of the shorter triplet repeat correlated significantly with age of onset (rS = -0.73, P < 0.0001), consistent with previous reports (2,3).
Median binocular high-contrast Snellen visual acuity equivalents (100% contrast level) did not differ between the FRDA and control groups (median Snellen equivalents = 20/16 in both groups). LCSLC scores, however, were significantly lower in the FRDA group for the aggregate letter score (LCSLC + high-contrast acuity, P < 0.0001, Wilcoxon rank sum test) and at each low-contrast level (5% chart:P = 0.0006; 1.25% chart:P < 0.0001; 0.6% chart:P < 0.0001) (Fig. 1, Table 1). The magnitude of the differences between groups increased with progressively lower contrast levels.
We then assessed correlations between LCSLC scores and FRDA disease features. In linear regression models accounting for patient age (Wald test), ambulation status predicted LCSLC scores to a significant degree (Fig. 2, Table 2). Specifically, wheelchair use was associated with a lower LCSLC score for each chart and for the aggregate score [LCSLC + high-contrast acuity, R2 = 0.38, P = 0.0015; 100% chart (high-contrast acuity), R2 = 0.42, P = 0.0011; 5% chart, R2 = 0.25, P = 0.020; 1.25% chart, R2 = 0.41, P = 0.0010; 0.6% chart, R2 = 0.23, P = 0.041]. Values for R2 in these regression models correspond to relatively high R values for human disease (R = 0.50–0.65);R2 indicates the proportion of the variability in LCSLC scores that is explained by ambulation status and age. In contrast, patient age correlated minimally and nonsignificantly with high-contrast acuity and LCSLC scores (rS = -0.26 for aggregate score;rS = -0.30 for 100% chart;rS = -0.14 for the 5% chart;rS = -0.25 for the 1.25%;rS = -0.20 for the 0.6%). The length of the patient's shorter triplet repeat demonstrated no correlation with LCSLC scores (rS = -0.0078 for aggregate LCSLC + high-contrast acuity score, all P values > 0.5). Disease duration correlated moderately with LCSLC scores (rS = -0.42 for aggregate score, P = 0.017;rS = -0.47 for 100%, P = 0.0073;rS = -0.24 for 5%, P = 0.19;rS = -0.40, P = 0.026 for 1.25% chart;rS = -.39, P = 0.028 for 0.6% chart). This demonstrates that LCSLC scores are more likely to reflect levels of disability and neurologic impairment (ambulation and disease duration) rather than biochemical or genetic features (such as triplet repeat length).
The results of this investigation demonstrate that contrast letter acuity as measured using the Low-Contrast Sloan Letter Charts (LCSLC) provides a useful measure for assessment of visual dysfunction in FRDA. LCSLC scores were significantly lower among patients with FRDA compared with age-matched, visually asymptomatic volunteers. Among FRDA patients, LCSLC scores also correlated with disease duration and were predicted significantly by ambulation status in linear regression models accounting simultaneously for age. LCSLC scores did not correlate with triplet repeat length and correlated minimally with age. This result suggests that visual dysfunction in FRDA, as measured by the LCSLC, is associated with progressive features of the disease. LCSLC testing therefore demonstrates excellent potential as a candidate visual outcome measure in FRDA, analogous to its proposed role in multiple sclerosis (15).
The ability of LCSLC scores to discriminate between FRDA patients and controls was greatest for the 5% charts and 1.25% charts, suggesting that LCSLC may be most useful at these contrast levels. Conversely, binocular high-contrast visual acuity scores (100% chart) were similar between FRDA patients and controls, emphasizing that traditional measures of visual acuity may not entirely capture visual dysfunction in patients with FRDA.
Patients and control participants in this study wore their habitual distance correction (glasses or contact lenses) for LCSLC testing and did not receive detailed refractions. Although differences in LCSLC scores between the FRDA and control groups at low-contrast levels could potentially reflect differences in access to routine ophthalmologic care, the following evidence suggests that the observed differences are likely to reflect underlying visual pathway disease in FRDA: 1) median Snellen equivalents (used for nonresearch refraction techniques) were equal between the FRDA and control groups in this study; 2) in an ongoing cross-sectional study of visual outcome measures in multiple sclerosis (24), LCSLC scores at low-contrast levels were significantly lower (worse) among patients than among age-matched controls, even after detailed refractions. Future studies of LCSLC testing in patients with FRDA and other neuro-ophthalmologic disorders could include detailed refractions and an assessment of efferent visual abnormalities.
Whereas ambulation status predicted LCSLC scores in linear regression models accounting for age, there was substantial variability in scores within each ambulation category (Fig. 2). This indicates that LCSLC testing in patients with FRDA may capture aspects of disease that are not entirely captured by ambulation status alone. LCSLC testing is also a convenient yet cost effective measure to add to clinical outcome scales in FRDA. The charts are portable (14 x 14 inches), and testing may be administered by nonphysician professionals within a 10- to 15-minute time period.
Visual dysfunction has been noted as an aspect of neurologic dysfunction in FRDA. However, traditional assessments note largely subclinical visual loss with abnormalities detected by electrophysiological testing in up to 90% of patients (1,5–9). Based on studies of patients with optic neuropathy and severe visual loss, the sites of afferent visual dysfunction in FRDA are thought to be the optic nerve and pregeniculate visual pathways. Since efferent (ocular motor) pathways are also affected in FRDA, visual dysfunction as captured by binocular LCSLC testing may also result from convergence or fixation abnormalities. However, whether the site of the abnormality is afferent or efferent, the correlation with ambulation status and disease duration demonstrates that LCSLC capture a component of progressive disability in FRDA. A clear correlation of visual dysfunction with disease duration and disability has not always been noted in previous studies on vision in FRDA (7,9). LCSLC may therefore be sensitive to disease progression even in patients whose ambulation status can no longer be measured.
The lack of correlation between shorter triplet repeat length and LCSLC scores seems paradoxical. This discrepancy most likely reflects a selection bias in our patient population because the most severely affected individuals (those with longest triplet repeat length and long disease durations) may not seek ongoing medical care at tertiary care centers and therefore are not included in our study. In our patient cohort, shorter triplet repeat length was highly inversely correlated with disease duration (data not shown). Because disease duration affects LCSLC scores, this observation may explain the lack of correlation of the GAA triplet repeat length with visual function in our patients.
The results of this investigation provide quantitative evidence that a measure of visual function, specifically the LCSLC, should be considered for use in future clinical trials of therapies for FRDA. The usefulness of LCSLC testing for longitudinal assessment of patients with neurologic disorders, including FRDA, remains to be determined and is under examination in ongoing multiple sclerosis clinical trials. Future studies of FRDA patients with the use of standardized clinical outcome measures, detailed refractions, and quantitative assessment of efferent visual abnormalities will be crucial in determining the extent and nature of visual dysfunction in FRDA in the broader context of neurologic impairment.
This work was supported by grants NS01789 and EY00351 from the National Institutes of Health, a grant from the Muscular Dystrophy Association, and a Beeson Scholar Award.
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